New class may help smokers quit, curb post-cessation weight gain

May 04, 2004

In phase 3 trials, the first agent in a novel class known as the selective
cannabinoid type 1 receptor blockers doubled the odds of quitting smoking
while reducing post-cessation weight gain compared with placebo. The agent,
rimonabant, also improved several features of the metabolic syndrome in
patients with abdominal obesity, reported researchers at the 53rd Annual
Scientific Session of the American College of Cardiology (ACC).

Chronic nicotine use leads to overstimulation of the endocannabinoid
system, which plays a critical role in regulation of food intake and energy
expenditure. "Rimonabant might restore the balance in that disturbed
endocannabinoid system," said Robert M. Anthenelli, MD, associate professor
of psychiatry and neuroscience, University of Cincinnati, and lead investigator
of one of the studies presented at ACC.

In one study, 787 people who smoked at least 2 packs of cigarettes per
day and expressed a desire to quit but were previously unable to do so were
randomized to once-daily doses of rimonabant, 5 mg; rimonabant, 20 mg; or
placebo. Treatment was initiated 2 weeks prior to the attempt at smoking
cessation and was continued for another 8 weeks.

The cessation rates were 27.6% among the patients assigned 20 mg of rimonabant
and 16.1% among the placebo recipients (P=.004). The 5-mg dose of rimonabant
had no effect on the cessation rate.

Overweight and obese patients lost weight on rimonabant during the 10
weeks of treatment while normal weight smokers did not. Overweight smokers
assigned to rimonabant experienced a weight loss of 0.5 kg versus a weight
gain of 0.9 kg in the placebo group. Obese patients randomized to rimonabant
lost 0.6 kg versus a weight gain of 1.3 kg among obese patients randomized
to placebo (P<.001).

In terms of adverse effects, nausea was more common with rimonabant compared
to placebo (15.7% vs 9.2%), as was upper respiratory tract infection (10.0%
vs 5.7%).

Rimonabant was also studied in 1,036 untreated dyslipidemic patients
with central obesity and a BMI of 27­40 kg/m2. The patients were randomized
to once-daily placebo or the 5- or 20-mg dose of rimonabant for 1 year.
Patients randomized to 20 mg of rimonabant lost a mean of 20 lb and 3.4
inches in waist circumference from baseline, which was significantly greater
compared to placebo (P<.001), said lead investigator Jean-Pierre Desprès,
PhD, director of research, department of cardiology, Université Laval,
Quebec City, Montreal.

The patients receiving 20 mg/d of rimonabant also demonstrated an improvement
in their lipid profiles. These patients experienced a 23% increase in high-density
lipoprotein (HDL) cholesterol and a 15% reduction in triglycerides from
baseline. In addition, rimonabant 20 mg was associated with a favorable
shift in low-density lipoprotein (LDL) particle size, from smaller atherogenic
particles to larger, less atherogenic LDL particles. Because of these lipid
changes, "we saw a 50% decrease in the number of patients who met the
criteria for metabolic syndrome, from 52.9% to 25.8%," said Dr Desprès.

Because cannabinoid receptors are expressed in adipose tissue, adiponectin
was measured in a subset of patients. "Adiponectin levels are markedly
reduced in abdominally obese patients," Dr Desprès said. In
the 20-mg rimonabant group, plasma adiponectin increased by 41% compared
with an increase of only 13.6% in the placebo group (P<.001).

"This increase in adiponectin may explain the effect of the drug
on cardiovascular risk factors," said Dr Desprès.